rs149775942

Variant names:

• chr12-12718265-G-A
• rs149775942
• NM_004064.5:c.426G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-12718265-G-A
• chr12-12718265-G-C
• chr12-12718265-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004064.5(CDKN1B):​c.426G>A​(p.Thr142Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00517 in 1,609,008 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T142T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0035 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (33 hom.)
• Consequence: CDKN1B NM_004064.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 2.09
• Publications: 6 publications found

Genes affected

CDKN1B (HGNC:1785): (cyclin dependent kinase inhibitor 1B) This gene encodes a cyclin-dependent kinase inhibitor, which shares a limited similarity with CDK inhibitor CDKN1A/p21. The encoded protein binds to and prevents the activation of cyclin E-CDK2 or cyclin D-CDK4 complexes, and thus controls the cell cycle progression at G1. The degradation of this protein, which is triggered by its CDK dependent phosphorylation and subsequent ubiquitination by SCF complexes, is required for the cellular transition from quiescence to the proliferative state. Mutations in this gene are associated with multiple endocrine neoplasia type IV (MEN4). [provided by RefSeq, Apr 2014]

CDKN1B Gene-Disease associations (from GenCC):

• multiple endocrine neoplasia type 4

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• multiple endocrine neoplasia

  Inheritance: AD Classification: STRONG Submitted by: G2P
• hereditary nonpolyposis colon cancer

  Inheritance: Unknown Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 12-12718265-G-A is Benign according to our data. Variant chr12-12718265-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 239622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.09 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00351 (535/152358) while in subpopulation NFE AF = 0.00528 (359/68032). AF 95% confidence interval is 0.00483. There are 1 homozygotes in GnomAd4. There are 229 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 535 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004064.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1B	NM_004064.5	MANE Select	c.426G>A	p.Thr142Thr	synonymous	Exon 1 of 3	NP_004055.1	Q6I9V6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1B	ENST00000228872.9	TSL:1 MANE Select	c.426G>A	p.Thr142Thr	synonymous	Exon 1 of 3	ENSP00000228872.4	P46527
	CDKN1B	ENST00000396340.1	TSL:3	c.426G>A	p.Thr142Thr	synonymous	Exon 1 of 2	ENSP00000379629.1	E7ES52
	CDKN1B	ENST00000614874.2	TSL:6	c.426G>A	p.Thr142Thr	synonymous	Exon 1 of 2	ENSP00000507272.1	P46527

Frequencies

GnomAD3 genomes AF: 0.00351 AC: 534 AN: 152240 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00526

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00364 AC: 890 AN: 244544 AF XY: 0.00380

Gnomad AFR exome AF: 0.00101

Gnomad AMR exome AF: 0.00229

Gnomad ASJ exome AF: 0.0148

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000409

Gnomad NFE exome AF: 0.00536

Gnomad OTH exome AF: 0.00363

GnomAD4 exome AF: 0.00534 AC: 7782 AN: 1456650 Hom.: 33 Cov.: 39 AF XY: 0.00525 AC XY: 3806 AN XY: 724826

African (AFR) AF: 0.000926 AC: 31 AN: 33478

American (AMR) AF: 0.00253 AC: 113 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0157 AC: 411 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.000672 AC: 58 AN: 86256

European-Finnish (FIN) AF: 0.000394 AC: 19 AN: 48258

Middle Eastern (MID) AF: 0.0125 AC: 72 AN: 5768

European-Non Finnish (NFE) AF: 0.00610 AC: 6782 AN: 1111970

Other (OTH) AF: 0.00489 AC: 295 AN: 60364

GnomAD4 genome AF: 0.00351 AC: 535 AN: 152358 Hom.: 1 Cov.: 32 AF XY: 0.00307 AC XY: 229 AN XY: 74512

African (AFR) AF: 0.00115 AC: 48 AN: 41594

American (AMR) AF: 0.00412 AC: 63 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10624

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00528 AC: 359 AN: 68032

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00605 Hom.: 2

Bravo AF: 0.00395

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00502

EpiControl AF: 0.00480

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	Multiple endocrine neoplasia type 4 (8)
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Hereditary nonpolyposis colon cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	7.7
DANN	Benign	0.95
PhyloP100		2.1
PromoterAI		0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs149775942; hg19: chr12-12871199; COSMIC: COSV104563836;